rs267607789
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000249.4(MLH1):c.790+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
NM_000249.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.790+1G>A | splice_donor_variant | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.790+1G>A | splice_donor_variant | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152090Hom.: 0 Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000214 AC: 3AN: 1403754Hom.: 0 Cov.: 24 AF XY: 0.00000142 AC XY: 1AN XY: 701832
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74422
ClinVar
Submissions by phenotype
not provided Pathogenic:7
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 05, 2023 | Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Identified in individuals with MLH1-related cancers with concordant immunohistochemistry in published literature (Cummingham et al., 2001; Ward et al., 2002; Casey et al., 2005; Sanchez de Abajo et al., 2006; Ewald et al., 2007; Sheng et al., 2009; Alvarez et al., 2010; Haraldsdottir et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15200905, 15849733, 17440950, 16142001, 12200596, 15289847, 18692554, 18726168, 16341804, 18713544, 16276679, 12658575, 25525159, 25107687, 25133505, 25338684, 32549215, 31830689, 32294063, 17054581, 19248199, 16288214, 15955785, 20587412, 20937110, 15872200, 15713769, 9057658, 11524701, 26895986, 28874130, 28248820, 26666765, 20305446, 29887214, 30093976, 34178123, 32490589, 30787465, 16395668) - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 01, 2023 | The MLH1 c.790+1G>A variant (also known as IVS9+1G>A) disrupts a canonical splice site and has been shown to cause an in-frame skipping of exons 9-10 (PMID: 16395668 (2006)), at a level greater the alternatively spliced isoforms observed in normal cells (PMIDs: 9490293 (1998), 7728749 (1995)). The frequency of this variant in the general population, 0.0000066 (1/152090 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. The variant has been reported in multiple individuals with colorectal cancer or Lynch syndrome (PMIDs: 26895986 (2016), 25133505 (2014), 25107687 (2014), 24344984 (2013), 20937110 (2010), 20305446 (2010), 17054581 (2006), 16395668 (2006), 15955785 (2005), 15849733 (2005), 11524701 (2001)). A functional study also indicates the variant causes a significant loss of DNA mismatch repair activity (PMID: 11781295 (2002)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 17, 2023 | This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. Functional studies indicate this variant impacts protein function [PMID: 8574961, 11781295]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 19, 2022 | - - |
Lynch syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 15, 2016 | Variant summary: The MLH1 c.790+1G>A variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant ablishes the 5' splicing donor site, which was confirmed by an in vitro study (Auclair_2006). This variant has been found in numerous LS patients and is absent in 115338 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Variant causes splicing aberration interrupting protein function: full inactivation of variant allele - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 14, 2021 | The c.790+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 9 of the MLH1 gene. This mutation has been seen in multiple individuals with personal and family histories of colon cancer (Cunningham JM et al. Am. J. Hum. Genet. 2001 Oct;69:780-90; Rosty C et al. BMJ Open. 2016 Feb;6(2):e010293; Haraldsdottir S et al. Fam. Cancer 2016 Apr;15(2):253-60; Rossi BM et al. BMC Cancer 2017 Sep;17(1):623). In addition, a functional study utilizing RNA from an individual carrying this mutation found that it leads to skipping of coding exons 9 and 10 (Auclair J et al. Hum. Mutat. 2006 Feb;27:145-54; Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 14, 2021 | This variant causes a G to A nucleotide substitution at the +1 position of intron 9 splice donor site of the MLH1 gene. Functional RNA studies have shown that this variant causes a skipping of exons 9 and 10 (PMID: 16395668, 20937110) at a level far greater than the low-level alternate splicing reported in normal cells (PMID: 7728749, 9490293). This alternate splicing results in the deletion of amino acids 227-295 and loss of mismatch repair activity of the MLH1 protein (PMID: 11781295). This variant has been reported in individuals affected with Lynch syndrome (PMID: 15955785, 16395668, 19248199, 20937110, 25107687, 26666765, 26895986, 28874130) and colorectal cancer (PMID: 11524701,15713769). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Lynch syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
Lynch-like syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Constitutional Genetics Lab, Leon Berard Cancer Center | Jul 01, 2019 | - - |
Colonic neoplasm Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Sep 12, 2021 | - - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change affects a donor splice site in intron 9 of the MLH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Lynch syndrome and colorectal cancer (PMID: 11524701, 15849733, 15955785, 17054581, 20937110, 24710284). This variant is also known as IVS9+1G>A. ClinVar contains an entry for this variant (Variation ID: 90356). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects MLH1 function (PMID: 11781295). Studies have shown that disruption of this splice site results in skipping of exons 9-10, but is expected to preserve the integrity of the reading-frame (PMID: 16395668). For these reasons, this variant has been classified as Pathogenic. - |
Endometrial carcinoma Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Feb 21, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at